Lupus (2015) 0,
1–8
http://lup.sagepub.com
REVIEW
Antiphospholipid syndrome, antiphospholipid antibodies and solid organ transplantation J Gonza´lez-Moreno1, JL Callejas-Rubio2, R Rı´ os-Ferna´ndez2 and N Ortego-Centeno2 1
Internal Medicine Department, Hospital Son Lla`tzer, Palma de Mallorca, Illes Balears, Spain; and 2Autoimmune Diseases Unit, Internal Medicine Department, Hospital Clı´ nico San Cecilio, Granada, Spain
Antiphospholipid syndrome is considered a high risk factor for any kind of surgery. Considering that all solid organ transplants are critically dependent on the patency of vascular anastomosis, there is much concern about the consequences this pro-thrombotic condition may have on transplantation. Relatively little information is available in the literature assessing the real risk that antiphospholipid syndrome or the presence of antiphospholipid antibodies represent in solid organ transplantation. The aim of this article is to review the literature related to transplantation of solid organs in patients diagnosed with antiphospholipid syndrome or patients with positive antiphospholipid antibodies. Lupus (2015) 0, 1–8. Key words: Antiphospholipid syndrome; solid organ transplantation; thrombophilia; anticardiolipin antibodies; lupus anticoagulant
Introduction Antiphospholipid syndrome (APS) is an autoimmune disease defined by the occurrence of venous and arterial thrombosis, often multiple, and recurrent fetal loss, frequently accompanied by moderate thrombocytopenia, in the presence of antiphospholipid (aPL) antibodies, namely lupus anticoagulant (LA), anticardiolipin (aCL) antibodies, or anti-B2 glycoprotein-I (aB2GPI) antibodies.1 APS may occur in isolation, or in association with systemic lupus erythematosus (SLE) or other autoimmune conditions, where it is sometimes referred to as ‘‘secondary.’’2 Surgery could increase the risk of thrombosis in patients with APS owing to a number of factors: withdrawal of oral anticoagulants, induction of a transient hypercoagulability state, even despite ongoing anticoagulant therapy, or catastrophic exacerbation of APS (CAPS). Bleeding complications can also occur during the perioperative period due to excessive anticoagulation and/or thrombocytopenia.
Correspondence to: Juan Gonza´lez-Moreno, Hospital Son Lla`zter, Carretera de Manacor, Km4, Palma de Mallorca, Illes Balears, 07198, Spain. Email: [email protected] Received 16 October 2014; accepted 17 June 2015
Although there has been relatively little discussion of APS in organ transplantation, it is certain that there is an as yet undefined risk of allograft thrombosis for the APS patient. Considering that all solid organ transplants are critically dependent on the patency of vascular anastomosis, there is much concern about the consequences of a prothrombotic condition like APS on transplantation. The aim of this article is to review the literature related to transplantation of solid organs in patients diagnosed with APS or patients carrying aPL antibodies. As experience in kidney transplantation is wide, we have focused our review on other solid organs and have included a brief summary of the published evidence on APS/aPL antibodies and kidney transplantation.
Liver transplantation Hepatic vessel thrombosis, of either the portal vein or hepatic artery, occurs in 0.3%–12% of liver transplants in adults and it frequently results in graft loss.3,4 The etiology is usually multifactorial and includes local vessel injury as a result of surgery, recurrent hepatocellular carcinoma as well as hematological changes such as the presence of procoagulant factors. One of the recognized causes of
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venous thrombosis in the liver transplant setting includes APS (Table 1). Little has been published about the safety of liver transplantation in patients previously diagnosed with APS. Talenti et al. reported a case of a 47-year-old woman with a 30-year history of cryptogenic cirrhosis that was diagnosed with APS a few days before liver transplantation.5 The patient presented with a cerebral infarction with positive aCL antibodies and LA. Neither anticoagulation nor antiaggregation was initiated because of impending liver transplantation. No complications were reported during surgery and four months after the surgical procedure clearance both of aCL antibodies and LA was reported. Later Yasutomi et al. reported a successful living donor liver transplantation in a child previously diagnosed with APS.6 Immediately after liver transplantation a heparin drip was started, which was later switched to oral warfarin. During a followup of just three months no complications were observed. On the other hand, there are several publications assessing the relationship of vascular complications during or after liver transplantation and the presence of aPL antibodies. According to the most recent data, aCL antibodies are observed among 8.5% of liver transplant patients.7 However, the exact relationship between the presence of aCL antibodies or other aPL antibodies without other criteria of APS and the presence of vascular complications after liver transplantation has not been assessed. The presence of aPL antibodies has been reported in the plasma of individuals with chronic liver disease such as chronic hepatitis C virus (HCV) infection,8,9 chronic autoimmune liver disease10,11 and alcoholic liver disease.12,13 The pathophysiological significance of these antibodies in individuals with these liver diseases is unclear. Specifically, whether they represent an important dysregulation of the immune system or simply represent an epiphenomenon remains undefined. An association between aCL antibodies and hepatic artery thrombosis (HAT) after liver transplantation was first suggested by Pascual et al.14 They found that all seven patients who developed HAT after liver transplantation had positive aCL antibodies in contrast to 15/28 (53.6%) liver recipients who did not develop HAT. In addition, aCL antibodies titers were higher among those who developed HAT. This study suggests that the predictive value of positive aCL antibodies tests before liver transplantation is low, but the predictive value of a negative test is much higher.
Later Collier et al. reported two cases of liver graft loss due to HAT probably secondary to APS (both with confirmed LA and aCL antibodies).15 Vivarelli et al. described three cases of repeated HAT secondary to APS.16 In their institution 24/ 629 (3.8%) of liver-transplant patients underwent re-transplantation because of HAT. Out of those, three (12.5%) showed positive LA, aCL antibodies or aB2GPI antibodies. However, other series did not support the relationship between aPL antibodies and the presence of liver transplantation-related vascular complications. For example, in the same study by Collier et al.,15 they retrospectively analyzed the presence of immunoglobulin (Ig)G aCL antibodies in 132 patients undergoing liver transplantation and found that hepatic vessel thrombosis occurred in 21/132 (15.9%) patients following liver transplantation, but none of them had other clinical features of APS, and aCL antibodies were uncommon. It is noteworthy that they only determined the presence of IgG aCL antibodies. Van Thiel et al. concluded after studying 12 patients (five with chronic HCV infection, four with alcoholic liver disease, two with primary biliary cirrhosis, and one with sclerosing cholangitis) with positive aPL antibodies awaiting liver transplant that the presence of aPL antibodies does not identify patients at high risk for posttransplant vascular thrombosis.17 Significantly, LA was not determined and no patient had identifiable aCL antibodies. They also found that aPL antibodies levels fell during transplantation and remained low or undetectable one month and one year after transplantation, probably due to the immune suppression administered to prevent allograft rejection. Ayala et al. conducted a thrombophilic study of 293 orthotropic liver transplants (OLT) and found a prevalence of 8.5% of aCL antibodies among the included patients.7 Fifty-eight (12.8%) patients developed a post-transplant thrombotic event, but no relationship with the presence of aCL antibodies was found. In this study LA and aB2GPI antibodies were not determined. Furman´czyk-Zawiska et al. observed that the prevalence of aPL antibodies in 33 liver recipients was greater than in the general population, as they found a prevalence ranging from 0% to 25% depending on the aPL antibodies type while in the general population such prevalence is estimated at 1%–8%.18 They found no relationship between the presence of aPL antibodies and the incidence of thrombosis.
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Table 1 Summary of published studies of liver transplantation in patients with antiphospholipid syndrome (APS) or patients carrying antiphospholipid (aPL) antibodies
Antiphospholipid syndrome
First author reference
Study type
Description
Talenti5
Case report.
Yasutomi6
Case report.
No complications in four months of follow-up after transplantation. No complications in three months of follow-up after transplantation. Multifocal avascular necrosis after transplantation. A case of CAPS five days after surgery. Intraoperative CAPS. aCL antibodies were positive in seven of seven patients with HAT versus 15/28 patients without HAT. Cases report: Graft lost related to aPL antibodies.Retrospective analysis: Two of 21 patients with hepatic vessel thrombosis showed positive aCL antibodies. Graft lost related to aPL antibodies. None of 12 patients with positive aPL antibodies presented complications. No relationship was found between aCL antibodies and post-transplant thrombosis. One-quarter of patients with thrombotic complications had positive aPL antibodies. Two cases of ischemic stroke after transplantation and in relation to aCL antibodies.
20
Antiphospholipid antibodies carriers
Mundo Villamil22 Gologorsky23 Pascual14
Case report. Case report. Case report. Retrospective analysis.
Collier15
Cases report (two cases) and retrospective analysis.
Vivarelli16 Van Thiel17
Cases report (three cases). Prospective study.
Ayala7 Furman´czyk-Zawiska18
Retrospective and prospective analysis. Prospective study.
Bronster19
Cases report (two cases).
aCL: anticardiolipin; CAPS: catastrophic APS; HAT: hepatic artery thrombosis.
Vascular complications other than HAT or hepatic vein thrombosis have been published. Bronster et al. reported two cases of ischemic stroke two months and two years after OLT presumably related to aCL antibodies.19 Mundo et al. reported a rare case of multifocal avascular necrosis (AVN) after liver transplantation.20 AVN was diagnosed five months after cessation of glucocorticoid therapy, and was then related to primary APS. No vascular complications appeared in the transplanted liver. Finally, surgical procedures have been described as one of the most common precipitating factors of CAPS,21 the most severe form of APS, so that this entity must be considered during and after liver transplantation. Villamil et al. reported a case of CAPS after OLT in a patient with previously known positive LA who was under treatment with acetylsalicylic acid (ASA) because of the presence of two episodes of transient ischemic attacks six months before OLT.22 OLT was performed using antithrombotic prophylaxis and ASA, and was maintained postoperatively. Five days after surgery, and although intense immunosuppression, ASA and anticoagulation were used, the patient developed a rapid succession of multiple occlusive events affecting the central nervous system, myocardium, gastrointestinal tract and skin. Later Gologorsky et al. presented a 62-year-old female patient with HCV-related cirrhosis23 who suffered
an intraoperative fulminant intracardiac and aortic thrombosis during liver transplantation. Posthumously the patient was found to have moderate IgM aCL antibodies levels so they suspected a fatal presentation (CAPS) of a previously undiagnosed APS after ruling out other hypercoagulable states. Globally, this review suggests that the presence of aPL antibodies is an uncommon cause of hepatic vessel thrombosis following liver transplantation, especially in patients without a previous diagnosis of APS. As aPL antibodies have been related to different chronic liver diseases, it is difficult to identify those liver transplant candidates who are at high risk for vascular complications after grafting, and therefore no recommendation can be given suggesting the screening of those antibodies previous to liver transplantation. Management of patients with previous diagnosis of APS awaiting liver transplantation will be discussed later.
Heart transplantation Fewer publications have addressed the influence of APS or aPL antibodies in heart transplantation (Table 2). Asherson et al. published data on three SLE patients with pulmonary hypertension who Lupus
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Table 2 Summary of published studies of cardiac transplantation or other cardiothoracic procedures in patients with antiphospholipid syndrome (APS) or patients carrying antiphospholipid (aPL) antibodies
Antiphospholipid syndrome
Antiphospholipid antibodies carriers
First author reference
Study type
Description
Pengo25 Erdozain27
Case report. Retrospective analysis.
Hegde28
Case series (nine cases).
Died before transplantation. More complications in patients with APS undergoing cardiac valve replacement. High rates of postoperative clinical events after cardiothoracic surgery were described. One-third of heart-lung transplants failed, showing positive aPL antibodies. No attempt to correlate transplant function with aPL antibodies status was undertaken.
Asherson24
Retrospective analysis.
26
Retrospective analysis.
McIntyre
received heart-lung transplants.24 Only one transplant failure was reported, in a patient with positive LA and high positive aCL antibodies. Neither of the two successful heart-lung recipients had LA or aCL antibodies. Pengo et al. reported their experience with a young man previously diagnosed with APS who experienced a severe myocardial infarction due to a thrombus in the descending coronary artery.25 Heart transplantation was considered because of a severe invalidating post-infarction cardiomyopathy. Attending to the high titers of aCL antibodies and LA, authors considered the use of plasma exchange and immunosuppression with cyclosporine and azathioprine. Plasma exchanges achieved a significant reduction of antibodies levels, but unfortunately, because of deterioration of kidney function, immunosuppressive therapy was discontinued, and the patient was discharged, dying at his home two days later. A retrospective study conducted by McIntyre et al. reported a high frequency (83%) of positive aPL antibodies (either IgG, IgM or IgA aCL antibodies, antiphosphatidyl serine and antiphosphatidyl ethanolamine) between 105 cardiac transplant patients, many of whom had more than one aPL antibodies isotype.26 However, no attempt to correlate transplant function or biopsy data with aPL antibodies status was undertaken. Erdozain et al. reported a high mortality rate between 32 patients diagnosed with APS undergoing cardiac valve replacement.27 Most complications were related to thrombosis and bleeding. Owing to the lack of power, a consequence of the small size of the study, identification of clinically meaningful predictors of adverse outcomes could not be identified. In particular, results suggested that primary APS could be related to a worse outcome.
Hegde et al. published a case series of nine APS patients with different types of major cardiovascular procedures (coronary artery bypass surgery and/or valvular surgery).28 They found that despite aggressive anticoagulation and lack of significant preoperative comorbidities, APS patients undergoing cardiothoracic surgery appear to have high rates of postoperative clinical events, especially thromboembolism, that was found to be the major cause of postoperative morbidity (three of nine patients presented with a thromboembolic complication). No mortality was found in this study after a one-year follow-up. Complications and mortality between APS patients during and after cardiac transplantation and cardiac surgery seems to be relatively frequent although there is scarce information in the medical literature. Therefore, rigorous consideration of the indication of surgery as well as strict and coordinated perioperative control of anticoagulant therapy is recommended.
Other solid organ and tissue transplantations Pancreas Except for rejection, graft thrombosis is one of the main reasons for graft loss following pancreas transplantation and it causes major morbidity.29 Thrombosis has been related to a low-flow state of the pancreas graft and to diabetes-associated hypercoagulability. Little is known about the role of prothrombotic disorders in pancreatic graft thrombosis, although it seems that transplant recipients with thrombophilia are particularly prone to graft thrombosis.29,30 To our knowledge only one article assessing pancreas transplantation is focused on the presence of aPL antibodies.31 In this study, Wullstein et al.
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reported successful simultaneous pancreas-kidney transplantation in two diabetic patients with positive aPL antibodies. In one of those patients APS was diagnosed before transplantation. History of various thrombosis events (unspecified sites) in the setting of positive LA and aCL antibodies was referred. The second patient presented a month after transplantation and in the setting of a cytomegalovirus infection with a deep venous thrombosis in his left leg. He showed just a positive LA, so APS diagnosis in that setting could not be made. A majority of pancreas transplant programs use some form of prophylaxis for pancreas thrombosis, but special care must be taken with patients with known thrombophilia. Skin As far as we know, there is only one case published in the literature describing the outcomes of autologous skin transplantation in APS.32 Fiehn et al. reported the case of a 34-year-old woman diagnosed with SLE and secondary APS presenting with a widespread cutaneous necrosis due to thrombosis of the microvasculature and cutaneous vasculitis. Successful transplantation was achieved after intensification of immunosuppressive treatment with high-dose prednisone and cyclosporine A, together with anticoagulation with heparin.
Kidney transplantation Plenty of data suggest that patients with end-stage renal disease (ESRD) with APS are at high risk for renal vascular thrombosis, graft failure and/or systemic thrombosis post-transplantation.33–38 The significance of aPL antibodies on short- and longterm allograft survival and function has been analyzed in some studies. Forman et al.39 have demonstrated that the presence of pre-transplant aCL antibodies does not impact post-transplant kidney function. However, they suggested that more research was required to address the significance of other aPL antibodies. Later, Vaidya et al. showed that circulating levels of aCL antibodies alone without thrombotic complications did not result in inferior allograft survival.40 More recently, Canaud et al.33 demonstrated that the presence of LA in kidney transplant recipients was associated with a greater risk of developing typical features of APS nephropathy on the allograft and especially thrombotic microangiopathy (TMA) in the
early post-transplant course, especially in patients with APS. Because of this enhanced risk, some experts recommend routine screening for aPL antibodies and LA in all patients prior to kidney transplantation,34,41,42 while others propose systematic aPL antibodies screening in any patient experiencing thromboembolic event previous to or following renal transplantation.33,43 Although reduced rates of graft thrombosis have been reported in APS recipients receiving perioperative heparin or warfarin,40,44 a corresponding increase in major bleeding has also been shown.43,44 Long-term allograft survival in APS is not influenced by the type of anticoagulation therapy used.40 Low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) are the preferred drugs because of their short half-life and facility of use. In addition Podolak et al. recently reported a case in which bivalirudin was successfully used during kidney transplantation in a patient with CAPS and heparin-induced thrombocytopenia.45 Evidence for treatment of APS-related renal TMA is limited to case reports and retrospective series. In APS-related allograft TMA, plasmaexchanges have been associated with a good response46 and may contribute to partial renal recovery.47 Eculizumab, a monoclonal antibody directed against the complement protein C5, is increasingly being used for prevention and treatment of post-transplant APS-related TMA, especially in patients with CAPS.48–51 Recent international guidelines for kidney transplantation do not include APS or any other thrombophilia among their recommendations.52,53
General perioperative considerations in APS patients APS patients are classified as a high-risk group for venous thromboembolism during the postoperative period. Perioperative thrombosis can occur because of withdrawal of oral anticoagulants, increased hypercoagulability despite optimal anticoagulant therapy or CAPS. In addition to thrombosis, lifethreatening bleeding complications can occur during the perioperative period due to anticoagulation or thrombocytopenia. According to current recommendations,54 asymptomatic carriers of aPL antibodies should receive thromboprophylaxis with usual doses of LMWH in high-risk situations, such as surgery. Lupus
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No established recommendations argue in favor of screening for aPL antibodies prior to general surgery, nor to transplant surgery. Indefinite antithrombotic therapy is recommended in patients with definite APS and prior thrombosis.54 There is no consensus regarding the optimal perioperative management of anticoagulation in APS. Erkan et al.55 recommended keeping to an absolute minimum the periods without anticoagulation and the use of physical methods such as intermittent venous compression. In the absence of study data that specifically address the issue of perioperative anticoagulation management in patients with APS, we highlight the utility of general consensus guidelines from the American College of Chest Physicians.56 Bridging therapy from oral anticoagulants to a short-acting anticoagulant, such as subcutaneous LMWH or intravenous UFH, is recommended in all APS patients. General recommendations are summarized in Table 3. For general, abdominal-pelvic or thoracic surgery patients at high risk for venous thromboembolism, as those with positive aPL antibodies (especially in those with a high-risk serologic profile) who are not anticoagulated and who are not at high risk for major bleeding complications, the current recommendation is to start pharmacologic prophylaxis with LMWH or low-dose
Table 3 General perioperative considerations in APS patients Preoperative assessment Prolonged activated partial thromboplastin time and/or slightly prolonged prothrombin time when known to be due to APS are not contraindications for surgical procedures. Platelet count >100 109/l due to APS requires no specific therapy; thrombocytopenia does not protect against thrombosis. Multidisciplinary management (hematologist, rheumatologist, internist, surgeon) is recommended. Perioperative considerations Minimize intravascular manipulation for access and monitoring. Maintain high suspicion that any deviation from a normal course may reflect arterial or venous thrombosis Perioperative anticoagulation Keep periods without anticoagulation to an absolute minimum. VKA should be stopped approximately 5 days before surgery and anticoagulation with LMWH or UFH should be started. The last preoperative dose of LMWH should be administered approximately 24 hours before surgery. UFH should be stopped four to six hours before surgery. Be aware that patients with APS can develop recurrent thrombosis despite appropriate prophylaxis. VKA should be resumed approximately 12 to 24 hours after surgery (evening of or next morning) and when there is adequate hemostasis. Therapeutic-dose LMWH should be resumed 48 to 72 hours after surgery.
APS: antiphospholipid syndrome; LMWH: low-molecular-weight heparin; UFH: unfractionated heparin; VKA: vitamin K antagonists.
unfractionated heparin (LDUH). Mechanical prophylaxis with elastic stockings or intermittent pneumatic compression should be added to pharmacologic prophylaxis.56
Summary Most evidence about the relationship of APS and transplantation comes from the experience in kidney transplantation. The available data suggest that although the presence of aPL antibodies increases the risk of thrombotic complications after renal transplantation, patients with APS are at the highest risk. Therefore, screening for aPL antibodies should be carried out in patients with previous history of thrombosis and/or obstetric complications. Anticoagulation is highly recommended in APS patients undergoing kidney transplantation but close monitoring is essential. In addition this review suggests that the presence of aPL antibodies is an uncommon cause of hepatic vessel thrombosis following liver transplantation. As aPL antibodies have been related to different chronic liver diseases, screening for those antibodies prior to liver transplantation is not recommended. Little experience has been published assessing other kinds of organ transplantation (such as heart or pancreas) in APS or aPL antibodies carriers. Experience in liver and especially in kidney transplantation can lead us to suggest that screening for aPL antibodies prior to organ transplantation should be carried out only in high-risk patients (like patients with prior history of thrombosis). APS is considered to be one of the most prothrombotic disorders, especially when the ‘‘triple positivity’’ is present.57 In order to know the real risk of thrombotic complications related to solid organ transplantation, well-designed studies determining all three antibodies included in APS criteria (LA, aCL and aB2GPI) prior to surgery are needed. General management of APS patients has been previously summarized and includes a multidisciplinary approach and close monitoring of anticoagulation.
Conflict of interest statement The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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Funding The authors received no financial support for the research, authorship, and/or publication of this article.
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8 42 Kfoury E, Taher A, Saghieh S, Otrock ZK, Mahfouz R. The impact of inherited thrombophilia on surgery: A factor to consider before transplantation? Mol Biol Rep 2009; 36: 1041–1051. 43 Morrissey PE, Ramirez PJ, Gohh RY, et al. Management of thrombophilia in renal transplant patients. Am J Transplant 2002; 2: 872–876. 44 Friedman GS, Meier-Kriesche HU, Kaplan B, et al. Hypercoagulable states in renal transplant candidates: Impact of anticoagulation upon incidence of renal allograft thrombosis. Transplantation 2001; 72: 1073–1078. 45 Podolak B, Blickstein D, Inbal A, et al. Renal transplantation in a patient with catastrophic antiphospholipid syndrome and heparininduced thrombocytopenia. Isr Med Assoc J 2014; 16: 61–62. 46 Ruffatti A, Marson P, Valente M, et al. Plasma exchange in a patient with primary antiphospholipid syndrome undergoing kidney transplantation. Transpl Int 2007; 20: 475–477. 47 Chew CG, Bannister KM, Mathew TH, Russ G, Seymour A. Thrombotic microangiopathy related to anticardiolipin antibody in a renal allograft. Nephrol Dial Transplant 1999; 14: 436–438. 48 Lonze BE, Zachary AA, Magro CM, et al. Eculizumab prevents recurrent antiphospholipid antibody syndrome and enables successful renal transplantation. Am J Transplant 2014; 14: 459–465. 49 Lonze BE, Singer AL, Montgomery RA. Eculizumab and renal transplantation in a patient with CAPS. N Engl J Med 2010; 362: 1744–1745. 50 Canaud G, Kamar N, Anglicheau D, et al. Eculizumab improves posttransplant thrombotic microangiopathy due to antiphospholipid syndrome recurrence but fails to prevent chronic vascular changes. Am J Transplant 2013; 13: 2179–2185.
51 Hadaya K, Ferrari-Lacraz S, Fumeaux D, et al. Eculizumab in acute recurrence of thrombotic microangiopathy after renal transplantation. Am J Transplant 2011; 11: 2523–2527. 52 European Renal Best Practice Transplantation Guideline Development Group. ERBP Guideline on the Management and Evaluation of the Kidney Donor and Recipient. Nephrol Dial Transplant 2013; 28(Suppl 2): ii1–ii71. 53 Andrews PA, Burnapp L, Manas D, et al. Summary of the British Transplantation Society/Renal Association U.K. guidelines for living donor kidney transplantation. Transplantation 2012; 93: 666–673. 54 Ruiz-Irastorza G, Cuadrado MJ, Ruiz-Arruza I, et al. Evidencebased recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: Report of a task force at the 13th International Congress on antiphospholipid antibodies. Lupus 2011; 20: 206–218. 55 Erkan D, Leibowitz E, Berman J, Lockshin MD. Perioperative medical management of antiphospholipid syndrome: Hospital for special surgery experience, review of literature, and recommendations. J Rheumatol 2002; 29: 843–849. 56 Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuu¨nemann HJ American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141(2 Suppl): 7S–47S. 57 Forastiero R. Multiple antiphospholipid antibodies positivity and antiphospholipid syndrome criteria re-evaluation. Lupus 2014; 23: 1252–1254.
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http://lup.sagepub.com
REVIEW
Antiphospholipid syndrome, antiphospholipid antibodies and solid organ transplantation J Gonza´lez-Moreno1, JL Callejas-Rubio2, R Rı´ os-Ferna´ndez2 and N Ortego-Centeno2 1
Internal Medicine Department, Hospital Son Lla`tzer, Palma de Mallorca, Illes Balears, Spain; and 2Autoimmune Diseases Unit, Internal Medicine Department, Hospital Clı´ nico San Cecilio, Granada, Spain
Antiphospholipid syndrome is considered a high risk factor for any kind of surgery. Considering that all solid organ transplants are critically dependent on the patency of vascular anastomosis, there is much concern about the consequences this pro-thrombotic condition may have on transplantation. Relatively little information is available in the literature assessing the real risk that antiphospholipid syndrome or the presence of antiphospholipid antibodies represent in solid organ transplantation. The aim of this article is to review the literature related to transplantation of solid organs in patients diagnosed with antiphospholipid syndrome or patients with positive antiphospholipid antibodies. Lupus (2015) 0, 1–8. Key words: Antiphospholipid syndrome; solid organ transplantation; thrombophilia; anticardiolipin antibodies; lupus anticoagulant
Introduction Antiphospholipid syndrome (APS) is an autoimmune disease defined by the occurrence of venous and arterial thrombosis, often multiple, and recurrent fetal loss, frequently accompanied by moderate thrombocytopenia, in the presence of antiphospholipid (aPL) antibodies, namely lupus anticoagulant (LA), anticardiolipin (aCL) antibodies, or anti-B2 glycoprotein-I (aB2GPI) antibodies.1 APS may occur in isolation, or in association with systemic lupus erythematosus (SLE) or other autoimmune conditions, where it is sometimes referred to as ‘‘secondary.’’2 Surgery could increase the risk of thrombosis in patients with APS owing to a number of factors: withdrawal of oral anticoagulants, induction of a transient hypercoagulability state, even despite ongoing anticoagulant therapy, or catastrophic exacerbation of APS (CAPS). Bleeding complications can also occur during the perioperative period due to excessive anticoagulation and/or thrombocytopenia.
Correspondence to: Juan Gonza´lez-Moreno, Hospital Son Lla`zter, Carretera de Manacor, Km4, Palma de Mallorca, Illes Balears, 07198, Spain. Email: [email protected] Received 16 October 2014; accepted 17 June 2015
Although there has been relatively little discussion of APS in organ transplantation, it is certain that there is an as yet undefined risk of allograft thrombosis for the APS patient. Considering that all solid organ transplants are critically dependent on the patency of vascular anastomosis, there is much concern about the consequences of a prothrombotic condition like APS on transplantation. The aim of this article is to review the literature related to transplantation of solid organs in patients diagnosed with APS or patients carrying aPL antibodies. As experience in kidney transplantation is wide, we have focused our review on other solid organs and have included a brief summary of the published evidence on APS/aPL antibodies and kidney transplantation.
Liver transplantation Hepatic vessel thrombosis, of either the portal vein or hepatic artery, occurs in 0.3%–12% of liver transplants in adults and it frequently results in graft loss.3,4 The etiology is usually multifactorial and includes local vessel injury as a result of surgery, recurrent hepatocellular carcinoma as well as hematological changes such as the presence of procoagulant factors. One of the recognized causes of
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venous thrombosis in the liver transplant setting includes APS (Table 1). Little has been published about the safety of liver transplantation in patients previously diagnosed with APS. Talenti et al. reported a case of a 47-year-old woman with a 30-year history of cryptogenic cirrhosis that was diagnosed with APS a few days before liver transplantation.5 The patient presented with a cerebral infarction with positive aCL antibodies and LA. Neither anticoagulation nor antiaggregation was initiated because of impending liver transplantation. No complications were reported during surgery and four months after the surgical procedure clearance both of aCL antibodies and LA was reported. Later Yasutomi et al. reported a successful living donor liver transplantation in a child previously diagnosed with APS.6 Immediately after liver transplantation a heparin drip was started, which was later switched to oral warfarin. During a followup of just three months no complications were observed. On the other hand, there are several publications assessing the relationship of vascular complications during or after liver transplantation and the presence of aPL antibodies. According to the most recent data, aCL antibodies are observed among 8.5% of liver transplant patients.7 However, the exact relationship between the presence of aCL antibodies or other aPL antibodies without other criteria of APS and the presence of vascular complications after liver transplantation has not been assessed. The presence of aPL antibodies has been reported in the plasma of individuals with chronic liver disease such as chronic hepatitis C virus (HCV) infection,8,9 chronic autoimmune liver disease10,11 and alcoholic liver disease.12,13 The pathophysiological significance of these antibodies in individuals with these liver diseases is unclear. Specifically, whether they represent an important dysregulation of the immune system or simply represent an epiphenomenon remains undefined. An association between aCL antibodies and hepatic artery thrombosis (HAT) after liver transplantation was first suggested by Pascual et al.14 They found that all seven patients who developed HAT after liver transplantation had positive aCL antibodies in contrast to 15/28 (53.6%) liver recipients who did not develop HAT. In addition, aCL antibodies titers were higher among those who developed HAT. This study suggests that the predictive value of positive aCL antibodies tests before liver transplantation is low, but the predictive value of a negative test is much higher.
Later Collier et al. reported two cases of liver graft loss due to HAT probably secondary to APS (both with confirmed LA and aCL antibodies).15 Vivarelli et al. described three cases of repeated HAT secondary to APS.16 In their institution 24/ 629 (3.8%) of liver-transplant patients underwent re-transplantation because of HAT. Out of those, three (12.5%) showed positive LA, aCL antibodies or aB2GPI antibodies. However, other series did not support the relationship between aPL antibodies and the presence of liver transplantation-related vascular complications. For example, in the same study by Collier et al.,15 they retrospectively analyzed the presence of immunoglobulin (Ig)G aCL antibodies in 132 patients undergoing liver transplantation and found that hepatic vessel thrombosis occurred in 21/132 (15.9%) patients following liver transplantation, but none of them had other clinical features of APS, and aCL antibodies were uncommon. It is noteworthy that they only determined the presence of IgG aCL antibodies. Van Thiel et al. concluded after studying 12 patients (five with chronic HCV infection, four with alcoholic liver disease, two with primary biliary cirrhosis, and one with sclerosing cholangitis) with positive aPL antibodies awaiting liver transplant that the presence of aPL antibodies does not identify patients at high risk for posttransplant vascular thrombosis.17 Significantly, LA was not determined and no patient had identifiable aCL antibodies. They also found that aPL antibodies levels fell during transplantation and remained low or undetectable one month and one year after transplantation, probably due to the immune suppression administered to prevent allograft rejection. Ayala et al. conducted a thrombophilic study of 293 orthotropic liver transplants (OLT) and found a prevalence of 8.5% of aCL antibodies among the included patients.7 Fifty-eight (12.8%) patients developed a post-transplant thrombotic event, but no relationship with the presence of aCL antibodies was found. In this study LA and aB2GPI antibodies were not determined. Furman´czyk-Zawiska et al. observed that the prevalence of aPL antibodies in 33 liver recipients was greater than in the general population, as they found a prevalence ranging from 0% to 25% depending on the aPL antibodies type while in the general population such prevalence is estimated at 1%–8%.18 They found no relationship between the presence of aPL antibodies and the incidence of thrombosis.
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Table 1 Summary of published studies of liver transplantation in patients with antiphospholipid syndrome (APS) or patients carrying antiphospholipid (aPL) antibodies
Antiphospholipid syndrome
First author reference
Study type
Description
Talenti5
Case report.
Yasutomi6
Case report.
No complications in four months of follow-up after transplantation. No complications in three months of follow-up after transplantation. Multifocal avascular necrosis after transplantation. A case of CAPS five days after surgery. Intraoperative CAPS. aCL antibodies were positive in seven of seven patients with HAT versus 15/28 patients without HAT. Cases report: Graft lost related to aPL antibodies.Retrospective analysis: Two of 21 patients with hepatic vessel thrombosis showed positive aCL antibodies. Graft lost related to aPL antibodies. None of 12 patients with positive aPL antibodies presented complications. No relationship was found between aCL antibodies and post-transplant thrombosis. One-quarter of patients with thrombotic complications had positive aPL antibodies. Two cases of ischemic stroke after transplantation and in relation to aCL antibodies.
20
Antiphospholipid antibodies carriers
Mundo Villamil22 Gologorsky23 Pascual14
Case report. Case report. Case report. Retrospective analysis.
Collier15
Cases report (two cases) and retrospective analysis.
Vivarelli16 Van Thiel17
Cases report (three cases). Prospective study.
Ayala7 Furman´czyk-Zawiska18
Retrospective and prospective analysis. Prospective study.
Bronster19
Cases report (two cases).
aCL: anticardiolipin; CAPS: catastrophic APS; HAT: hepatic artery thrombosis.
Vascular complications other than HAT or hepatic vein thrombosis have been published. Bronster et al. reported two cases of ischemic stroke two months and two years after OLT presumably related to aCL antibodies.19 Mundo et al. reported a rare case of multifocal avascular necrosis (AVN) after liver transplantation.20 AVN was diagnosed five months after cessation of glucocorticoid therapy, and was then related to primary APS. No vascular complications appeared in the transplanted liver. Finally, surgical procedures have been described as one of the most common precipitating factors of CAPS,21 the most severe form of APS, so that this entity must be considered during and after liver transplantation. Villamil et al. reported a case of CAPS after OLT in a patient with previously known positive LA who was under treatment with acetylsalicylic acid (ASA) because of the presence of two episodes of transient ischemic attacks six months before OLT.22 OLT was performed using antithrombotic prophylaxis and ASA, and was maintained postoperatively. Five days after surgery, and although intense immunosuppression, ASA and anticoagulation were used, the patient developed a rapid succession of multiple occlusive events affecting the central nervous system, myocardium, gastrointestinal tract and skin. Later Gologorsky et al. presented a 62-year-old female patient with HCV-related cirrhosis23 who suffered
an intraoperative fulminant intracardiac and aortic thrombosis during liver transplantation. Posthumously the patient was found to have moderate IgM aCL antibodies levels so they suspected a fatal presentation (CAPS) of a previously undiagnosed APS after ruling out other hypercoagulable states. Globally, this review suggests that the presence of aPL antibodies is an uncommon cause of hepatic vessel thrombosis following liver transplantation, especially in patients without a previous diagnosis of APS. As aPL antibodies have been related to different chronic liver diseases, it is difficult to identify those liver transplant candidates who are at high risk for vascular complications after grafting, and therefore no recommendation can be given suggesting the screening of those antibodies previous to liver transplantation. Management of patients with previous diagnosis of APS awaiting liver transplantation will be discussed later.
Heart transplantation Fewer publications have addressed the influence of APS or aPL antibodies in heart transplantation (Table 2). Asherson et al. published data on three SLE patients with pulmonary hypertension who Lupus
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Table 2 Summary of published studies of cardiac transplantation or other cardiothoracic procedures in patients with antiphospholipid syndrome (APS) or patients carrying antiphospholipid (aPL) antibodies
Antiphospholipid syndrome
Antiphospholipid antibodies carriers
First author reference
Study type
Description
Pengo25 Erdozain27
Case report. Retrospective analysis.
Hegde28
Case series (nine cases).
Died before transplantation. More complications in patients with APS undergoing cardiac valve replacement. High rates of postoperative clinical events after cardiothoracic surgery were described. One-third of heart-lung transplants failed, showing positive aPL antibodies. No attempt to correlate transplant function with aPL antibodies status was undertaken.
Asherson24
Retrospective analysis.
26
Retrospective analysis.
McIntyre
received heart-lung transplants.24 Only one transplant failure was reported, in a patient with positive LA and high positive aCL antibodies. Neither of the two successful heart-lung recipients had LA or aCL antibodies. Pengo et al. reported their experience with a young man previously diagnosed with APS who experienced a severe myocardial infarction due to a thrombus in the descending coronary artery.25 Heart transplantation was considered because of a severe invalidating post-infarction cardiomyopathy. Attending to the high titers of aCL antibodies and LA, authors considered the use of plasma exchange and immunosuppression with cyclosporine and azathioprine. Plasma exchanges achieved a significant reduction of antibodies levels, but unfortunately, because of deterioration of kidney function, immunosuppressive therapy was discontinued, and the patient was discharged, dying at his home two days later. A retrospective study conducted by McIntyre et al. reported a high frequency (83%) of positive aPL antibodies (either IgG, IgM or IgA aCL antibodies, antiphosphatidyl serine and antiphosphatidyl ethanolamine) between 105 cardiac transplant patients, many of whom had more than one aPL antibodies isotype.26 However, no attempt to correlate transplant function or biopsy data with aPL antibodies status was undertaken. Erdozain et al. reported a high mortality rate between 32 patients diagnosed with APS undergoing cardiac valve replacement.27 Most complications were related to thrombosis and bleeding. Owing to the lack of power, a consequence of the small size of the study, identification of clinically meaningful predictors of adverse outcomes could not be identified. In particular, results suggested that primary APS could be related to a worse outcome.
Hegde et al. published a case series of nine APS patients with different types of major cardiovascular procedures (coronary artery bypass surgery and/or valvular surgery).28 They found that despite aggressive anticoagulation and lack of significant preoperative comorbidities, APS patients undergoing cardiothoracic surgery appear to have high rates of postoperative clinical events, especially thromboembolism, that was found to be the major cause of postoperative morbidity (three of nine patients presented with a thromboembolic complication). No mortality was found in this study after a one-year follow-up. Complications and mortality between APS patients during and after cardiac transplantation and cardiac surgery seems to be relatively frequent although there is scarce information in the medical literature. Therefore, rigorous consideration of the indication of surgery as well as strict and coordinated perioperative control of anticoagulant therapy is recommended.
Other solid organ and tissue transplantations Pancreas Except for rejection, graft thrombosis is one of the main reasons for graft loss following pancreas transplantation and it causes major morbidity.29 Thrombosis has been related to a low-flow state of the pancreas graft and to diabetes-associated hypercoagulability. Little is known about the role of prothrombotic disorders in pancreatic graft thrombosis, although it seems that transplant recipients with thrombophilia are particularly prone to graft thrombosis.29,30 To our knowledge only one article assessing pancreas transplantation is focused on the presence of aPL antibodies.31 In this study, Wullstein et al.
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reported successful simultaneous pancreas-kidney transplantation in two diabetic patients with positive aPL antibodies. In one of those patients APS was diagnosed before transplantation. History of various thrombosis events (unspecified sites) in the setting of positive LA and aCL antibodies was referred. The second patient presented a month after transplantation and in the setting of a cytomegalovirus infection with a deep venous thrombosis in his left leg. He showed just a positive LA, so APS diagnosis in that setting could not be made. A majority of pancreas transplant programs use some form of prophylaxis for pancreas thrombosis, but special care must be taken with patients with known thrombophilia. Skin As far as we know, there is only one case published in the literature describing the outcomes of autologous skin transplantation in APS.32 Fiehn et al. reported the case of a 34-year-old woman diagnosed with SLE and secondary APS presenting with a widespread cutaneous necrosis due to thrombosis of the microvasculature and cutaneous vasculitis. Successful transplantation was achieved after intensification of immunosuppressive treatment with high-dose prednisone and cyclosporine A, together with anticoagulation with heparin.
Kidney transplantation Plenty of data suggest that patients with end-stage renal disease (ESRD) with APS are at high risk for renal vascular thrombosis, graft failure and/or systemic thrombosis post-transplantation.33–38 The significance of aPL antibodies on short- and longterm allograft survival and function has been analyzed in some studies. Forman et al.39 have demonstrated that the presence of pre-transplant aCL antibodies does not impact post-transplant kidney function. However, they suggested that more research was required to address the significance of other aPL antibodies. Later, Vaidya et al. showed that circulating levels of aCL antibodies alone without thrombotic complications did not result in inferior allograft survival.40 More recently, Canaud et al.33 demonstrated that the presence of LA in kidney transplant recipients was associated with a greater risk of developing typical features of APS nephropathy on the allograft and especially thrombotic microangiopathy (TMA) in the
early post-transplant course, especially in patients with APS. Because of this enhanced risk, some experts recommend routine screening for aPL antibodies and LA in all patients prior to kidney transplantation,34,41,42 while others propose systematic aPL antibodies screening in any patient experiencing thromboembolic event previous to or following renal transplantation.33,43 Although reduced rates of graft thrombosis have been reported in APS recipients receiving perioperative heparin or warfarin,40,44 a corresponding increase in major bleeding has also been shown.43,44 Long-term allograft survival in APS is not influenced by the type of anticoagulation therapy used.40 Low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) are the preferred drugs because of their short half-life and facility of use. In addition Podolak et al. recently reported a case in which bivalirudin was successfully used during kidney transplantation in a patient with CAPS and heparin-induced thrombocytopenia.45 Evidence for treatment of APS-related renal TMA is limited to case reports and retrospective series. In APS-related allograft TMA, plasmaexchanges have been associated with a good response46 and may contribute to partial renal recovery.47 Eculizumab, a monoclonal antibody directed against the complement protein C5, is increasingly being used for prevention and treatment of post-transplant APS-related TMA, especially in patients with CAPS.48–51 Recent international guidelines for kidney transplantation do not include APS or any other thrombophilia among their recommendations.52,53
General perioperative considerations in APS patients APS patients are classified as a high-risk group for venous thromboembolism during the postoperative period. Perioperative thrombosis can occur because of withdrawal of oral anticoagulants, increased hypercoagulability despite optimal anticoagulant therapy or CAPS. In addition to thrombosis, lifethreatening bleeding complications can occur during the perioperative period due to anticoagulation or thrombocytopenia. According to current recommendations,54 asymptomatic carriers of aPL antibodies should receive thromboprophylaxis with usual doses of LMWH in high-risk situations, such as surgery. Lupus
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No established recommendations argue in favor of screening for aPL antibodies prior to general surgery, nor to transplant surgery. Indefinite antithrombotic therapy is recommended in patients with definite APS and prior thrombosis.54 There is no consensus regarding the optimal perioperative management of anticoagulation in APS. Erkan et al.55 recommended keeping to an absolute minimum the periods without anticoagulation and the use of physical methods such as intermittent venous compression. In the absence of study data that specifically address the issue of perioperative anticoagulation management in patients with APS, we highlight the utility of general consensus guidelines from the American College of Chest Physicians.56 Bridging therapy from oral anticoagulants to a short-acting anticoagulant, such as subcutaneous LMWH or intravenous UFH, is recommended in all APS patients. General recommendations are summarized in Table 3. For general, abdominal-pelvic or thoracic surgery patients at high risk for venous thromboembolism, as those with positive aPL antibodies (especially in those with a high-risk serologic profile) who are not anticoagulated and who are not at high risk for major bleeding complications, the current recommendation is to start pharmacologic prophylaxis with LMWH or low-dose
Table 3 General perioperative considerations in APS patients Preoperative assessment Prolonged activated partial thromboplastin time and/or slightly prolonged prothrombin time when known to be due to APS are not contraindications for surgical procedures. Platelet count >100 109/l due to APS requires no specific therapy; thrombocytopenia does not protect against thrombosis. Multidisciplinary management (hematologist, rheumatologist, internist, surgeon) is recommended. Perioperative considerations Minimize intravascular manipulation for access and monitoring. Maintain high suspicion that any deviation from a normal course may reflect arterial or venous thrombosis Perioperative anticoagulation Keep periods without anticoagulation to an absolute minimum. VKA should be stopped approximately 5 days before surgery and anticoagulation with LMWH or UFH should be started. The last preoperative dose of LMWH should be administered approximately 24 hours before surgery. UFH should be stopped four to six hours before surgery. Be aware that patients with APS can develop recurrent thrombosis despite appropriate prophylaxis. VKA should be resumed approximately 12 to 24 hours after surgery (evening of or next morning) and when there is adequate hemostasis. Therapeutic-dose LMWH should be resumed 48 to 72 hours after surgery.
APS: antiphospholipid syndrome; LMWH: low-molecular-weight heparin; UFH: unfractionated heparin; VKA: vitamin K antagonists.
unfractionated heparin (LDUH). Mechanical prophylaxis with elastic stockings or intermittent pneumatic compression should be added to pharmacologic prophylaxis.56
Summary Most evidence about the relationship of APS and transplantation comes from the experience in kidney transplantation. The available data suggest that although the presence of aPL antibodies increases the risk of thrombotic complications after renal transplantation, patients with APS are at the highest risk. Therefore, screening for aPL antibodies should be carried out in patients with previous history of thrombosis and/or obstetric complications. Anticoagulation is highly recommended in APS patients undergoing kidney transplantation but close monitoring is essential. In addition this review suggests that the presence of aPL antibodies is an uncommon cause of hepatic vessel thrombosis following liver transplantation. As aPL antibodies have been related to different chronic liver diseases, screening for those antibodies prior to liver transplantation is not recommended. Little experience has been published assessing other kinds of organ transplantation (such as heart or pancreas) in APS or aPL antibodies carriers. Experience in liver and especially in kidney transplantation can lead us to suggest that screening for aPL antibodies prior to organ transplantation should be carried out only in high-risk patients (like patients with prior history of thrombosis). APS is considered to be one of the most prothrombotic disorders, especially when the ‘‘triple positivity’’ is present.57 In order to know the real risk of thrombotic complications related to solid organ transplantation, well-designed studies determining all three antibodies included in APS criteria (LA, aCL and aB2GPI) prior to surgery are needed. General management of APS patients has been previously summarized and includes a multidisciplinary approach and close monitoring of anticoagulation.
Conflict of interest statement The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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Funding The authors received no financial support for the research, authorship, and/or publication of this article.
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